The proposed investigation is designed to define the role of chemoattractants in the regulation of oxidative metabolic responses of human neutrophils. At relatively high concentrations, certain chemoattractants activate neutrophil oxidative metabolism with resultant release of reactive metabolites. Our preliminary experiments have established that preincubation of neutrophils with low concentrations of these chemoattractants suppressed and enhanced subsequent oxidative responses to chemotactic and non-chemotactic stimuli respectively. These observations suggest that active cellular regulatory processes resulting from initial encounters of neutrophils with chemoattractants, constrain release of inflammatory mediators during chemotactic migration while preserving and activating microbicidal oxidative responsiveness of the cells when they reach and are stimulated by the target. We propose to assess and compare various neutrophil oxidative responses-including superoxide release, hydroxyl radical generation, bactericidal activity, release of cytotoxic mediators and generation of chemiluminescence-in response to phagocytic, non-chemotactic soluble, and chemotactic stimuli after exposure of neutrophils to chemoattractants under a variety of conditions in vitro. We will also compare oxidative responses initiated by concentration gradients of chemoattractants to those initiated by fixed concentrations of chemoattractants. The objective is to identify and biochemically characterize cellular responses to chemoattractants which regulate subsequent oxidative metabolism. We shall determine the relationship of these regulatory processes to other neutrophil processes induced by chemoattractants. Our goal is to evaluate the physiological significance of chemotactically induced oxidative regulatory processes and of neutrophil oxidative responses initiated by chemoattractants. With this background, we shall assess the possibility that disruption of these processes leads to detrimental amplification of inflammation or compromised host defense against infection.